This proposal has two major areas of focus, the study of specific unresponsiveness induced in adult mice with antilymphocyte serum (ALS) and donor cellular antigen and the study of the role of blood transfusions on prolonging allograft survival. First, experiments will study the mechanisms involved in three models of specific unresponsiveness induced in adult mice. Adult thymectomized and non-thymectomized mice treated with ALS and low doses of donor bone marrow are specifically unresponsive to donor antigens as shown by prolonged skin allograft survival. These mice are not chimeras and exhibit anti-donor cell-mediated immunity (CMI). Non-thymectomized mice have donor specific suppressor cells, but suppressor cells are absent in the thymectomized marrow model. In contrast, thymectomized ALS treated mice injected with large doses of hybrid lymphoid cells are chimeras, exhibit no CMI and lack suppressor cells. Experiments will compare these models with reference to (1) their immune status using in vitro methods and (2) the genetic requirements for induction of unresponsiveness. Second, experiments will investigate the effect of pre-transplant blood transfusions on graft survival, using a skin allograft model in ALS treated mice. The effect of both non-specific and donor specific blood will be studied. Experiments will investigate (1) the optimal protocol for maximal prolongation (2) the genetic requirements to achieve maximal prolongation (3) the immune mechanisms involved in prolongation (4) the effect of prior transfusions on the induction of unresponsiveness in ALS treated mice injected with marrow. A final series of experiments in dogs will extend the principles defined in adult mice for induction of unresponsiveness to canine renal allografts. These experiments will investigate optimal protocols for prolonging renal allografts with ALS and marrow, use of cryopreserved marrow, concomitant immune suppression, effect of thymectomy and the use of spleen cells in place of marrow to induce unresponsiveness.